The treatment of malignant mesothelioma (MPM) remains inadequate. New therapies, such as gene therapy[unreadable] or immuno-gene therapy, are desperately needed. This Project is based on a previous series of Phase I[unreadable] clinical trials using recombinant, replication-deficient adenoviral (Ad) vectors containing the Herpes Simplex[unreadable] Thymidine Kinase (HSVtk) gene in 34 MPM patients. Significant intratumoral HSVtk gene transfer was[unreadable] achieved and some radiographic and clinical responses were noted, including 2 patients who had durable[unreadable] complete responses in delayed fashion, highly suggestive of anti-tumor immune responses. On this basis,[unreadable] the focus of laboratory and clinical work was shifted to genetic immunotherapy of thoracic malignancies.[unreadable] Based on strong preclinical data, a new Phase I clinical trial using a single dose of intrapleural adenoviral[unreadable] interferon beta (Ad.lFN-beta) for patients with MPM and malignant pleural effusions (MPE) was conducted.[unreadable] The approach was safe and a number of immunologic responses, as well as clinical responses were[unreadable] observed. The goal of this Project is to continue and extend these clinical trials aimed at patients with[unreadable] mesothelioma. In the first aim, a Phase 1 trial will be conducted to assess the safety, toxicity profile, immune[unreadable] responses, and clinical effect of two intrapleural doses of Ad.lFN-beta for patients with MPE/MPM. Specific[unreadable] Aims 2 and 3 will consist of Phase 2 clinical trials testing approaches in patients with MPM that were[unreadable] developed from our preclinical studies to augment efficacy. Aim 2 will determine the efficacy and immune[unreadable] responses associated with the delivery of two doses of Ad.lFN-beta as neo-adjuvant therapy in combination[unreadable] with surgical debulking and adjuvant COX-2 inhibitors in patients with MPM. Aim 3 will determine the[unreadable] efficacy and immune responses associated with the delivery of two doses of Ad.lFN-beta in combination with[unreadable] chemotherapy and adjuvant COX-2 inhibitors in patients with MPM. In Aim 4, investigators will begin the[unreadable] steps needed to develop an adoptive immunotherapy trial using genetically engineering T-lymphocytes[unreadable] reactive against mesothelin for patients with mesothelioma and other tumors expressing this tumor antigen[unreadable] after preclinical optimization.